1. Field of the Invention
The present invention relates to a pharmaceutical composition that is improved in its dissolution property, containing a compound that exhibits an inhibitory effect on activated blood coagulation factor X, and that is useful as a preventative and/or therapeutic drug for thrombotic diseases.
2. Description of Related Art
N1-(5-chloropyridin-2-yl)-N2-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamide represented by the following formula (I):
(in the present specification, the compound represented by formula (I) is also referred to as compound I) or a pharmacologically acceptable salt thereof, or a solvate thereof is known to exhibit an inhibitory effect on activated blood coagulation factor X (hereinafter, also referred to as FXa in the present specification) and be useful as a pharmaceutical drug, particularly, an activated blood coagulation factor X inhibitor (hereinafter, also referred to as an FXa inhibitor or anti-FXa in the present specification) and/or an agent for preventing and/or treating thrombosis or embolism (Patent Documents 1 to 6).
Compound I is a basic compound that exhibits favorable solubility in a strongly acidic aqueous solution, but reduced solubility in an aqueous solution having a pH in the neutral region (e.g., a neutral buffer). Therefore, a solid formulation containing compound I or a pharmacologically acceptable salt thereof, or a solvate thereof as an active ingredient exhibits a poor dissolution property of compound I or the pharmacologically acceptable salt thereof, or the solvate thereof in an aqueous solution having a pH in the neutral region. Methods for improving the dissolution rate of the active ingredient, comprising preparing a composition containing compound I combined with a sugar alcohol and/or a water-swelling additive (Patent Document 4), comprising coating a composition containing compound I with one or two or more coating agents selected from a cellulose derivative, a polyvinyl compound, an acrylic acid derivative, and a saccharide (Patent Document 4), or comprising adjusting the proportion of compound I or a pharmacologically acceptable salt thereof, or a solvate thereof in a pharmaceutical composition (Patent Document 5) are known as methods for improving such dissolution property in the neutral region of a solid formulation containing compound I or a pharmacologically acceptable salt thereof, or a solvate thereof as an active ingredient. Alternatively, it is known that the dissolution property in the neutral region of a solid formulation containing compound I or a pharmacologically acceptable salt thereof, or a solvate thereof as an active ingredient is improved by producing a granulated material containing compound I for use in the formulation under conditions for keeping the maximum water content of the granulated material during granulation at 10% or less (Patent Document 6).
Also, a sustained release formulation containing compound I is known as a formulation containing compound I (Patent Documents 7 to 9).